Human gp34 antigen belongs to a ligand family of tumor necrosis factor (referred to as "TNF" hereinbelow) classified as cytokine. Firstly, the gp34 antigen was identified as a human T-cell leukemia virus (referred to as HTLV-1 hereinbelow)-derived transcription activating factor p40Tax induced T-cell membrane glycoprotein of 34 kDa. Currently, the amino acid sequence of the gp34 antigen and DNA nucleotide sequence of the gene thereof are known (Tanaka et al: Int. J. Cancer 36, 549 (1985), Miura et al.: Mol. Cell. Biol. 11, 1313 (1991)). Meanwhile, the OX40 antigen has been identified as an activated T-cell antigen in rats (Paterson et al.: Mol. Immunol. 24, 1281 (1987)). Thereafter, it has been revealed that the gp34 antigen has a ligand-receptor relation with the OX40 antigen in humans and mice. The amino acid sequence of murine gp34 and the DNA nucleotide sequence of the gene thereof have been known (Godfrey et al.: J. Exp. Med. 180, 757 (1994), Baum et al.: EMBO J.13, 3992 (1994)). Furthermore, it has been elucidated at experimental autoimmune encephalomyelitis (referred to as "EAE" hereinafter)in rats that such OX40 antigen is expressed in an activated CD4-positive T-cell being contained in autoimmune diseases including multiple sclerosis, rheumatoid arthritis, sarcoidosis, autoimmune ocular diseases and inflammatory bowel disease and in graft-versus-host disease and functioning as autoimmunity, and that the specific elimination of the self-attacking CD4-positive T cells at an activated state by binding a cytotoxin to a substance recognizing such OX40 antigen may be promising as an effective therapeutic method. A patent application has been submitted therefor, while a report has also been issued (CANTAB PHARM, Res., Lim.: WO95/21251, Weinberg et al: Nature Med. 2, 183 (1996)). The report describes that a group of OX40-positive cells is present in activated CD4-positive T cells with self-reactivity among CD4-positive activated cells and an anti-OX40 immunotherapy against them may be effective as the therapeutic treatment of acute or chronic autoimmune diseases mediated via CD4-positive T cells. However, the report tells that the expression of OX40 is just a simple marker of cells responsible for autoimmune diseases and the therapeutic effect is owing to the elimination of target activated T cells. The report additionally tells that it is not yet elucidated whether or not such inflammatory state or autoimmune state can be suppressed by singly blocking the binding between gp34 and OX40 and that single addition of anti-OX antibody with no cytotoxin bound thereto did not suppress the cell growth of activated CD4-positive T lymphocytes responsible for the exacerbation of the symptomatic conditions. It is also reported that a rabbit anti-mouse OX40 polyclonal antibody bound with a cytotoxin suppressed the elevation of the score grading the symptomatic conditions in EAE, but no such effect is reported in a concurrently examined group dosed with only a rabbit anti-mouse OX40 polyclonal antibody or in a negative control alike. The finding indicates that it is not yet elucidated whether the inhibition of only the binding between gp34 and OX40 can suppress the inflammatory state or autoimmune state. Additionally, a patent application has been submitted, regarding a method for detecting inflammatory symptoms of a patient with a disease believed to be mediated with activated T lymphocytes, comprising examining an biopsy sample from the patient (CANTAB PHARM, Res, lim.: WO95/21251).
As has been described above, the functions of gp34 and OX 40 have been elucidated just partially. The relation between gp34 and OX40 and the role thereof in various autoimmune diseases have absolutely never been elucidated so far. Specific inhibition of the function mediated between these two molecules on the side of gp34 by using an anti-human gp34 monoclonal antibody has totally never been anticipated. In other words, it has never been known whether or not such inhibition is effective for the therapeutic treatment of autoimmune diseases including rheumatoid arthritis, multiple sclerosis, sarcoidosis, autoimmune uveitis and inflammatory bowel disease, and graft-versus-host disease.
Problems that the Invention is to Solve
It is an object of the invention to provide a novel pharmaceutical composition containing as the effective ingredient a human gp34 binding-inhibitory substance, more specifically a humanized anti-human gp34 monoclonal antibody, as a therapeutic agent for autoimmune disease including rheumatoid diseases including multiple sclerosis, sarcoidosis, autoimmune uveitis or inflammatory bowel disease, or graft-versus-host disease; and a method for therapeutically treating immune- or autoimmune diseases, comprising inhibiting binding to gp34, particularly binding to OX40.
Means for Solving the Problems
So as to overcome the problems, the inventors have made investigations. Consequently, the inventors have recovered a rat anti-mouse gp34 monoclonal antibody believed to have the same properties as those of a humanized monoclonal antibody binding to human gp34. Because gp34 experiments in patients with rheumatoid arthritis and multiple sclerosis cannot be practiced, ethically, the recovered rat anti-mouse gp34 monoclonal antibody was given to a collagen arthritis-triggered model mouse and an experimental autoimmune encephalomyelitis-triggered model mouse, whereby it was confirmed that the onset of the symptomatic conditions was suppressed in the rheumatoid model and the multiple sclerosis model. The finding firstly reveals that the binding between OX40 and gp34 on an OX40-positive activated T cell triggers autoimmune diseases such as rheumatism. The finding is indicated at the mouse experiments, but it is possibly suggested that the effect in mouse should also be exerted in humans because the properties of mouse gp34 and mouse OX40 are common to the properties of human gp34 and human OX40 in such a manner that gp34 and OX40 are in a relation between ligand and receptor. More specifically, the finding unconditionally indicates that a monoclonal antibody with binding potency to human gp34 is effective as a therapeutic agent for autoimmune diseases including rheumatoid arthritis, multiple sclerosis, sarcoidosis, autoimmune uveitis and inflammatory bowel disease, and graft-versus-host disease.
In other words, the present invention is a pharmaceutical composition containing as the effective ingredient a gp34 binding-inhibitory substance for the therapeutic treatment of autoimmune diseases, or a pharmaceutical composition containing as the effective ingredient a gp34 binding-inhibitory substance for the therapeutic treatment of immune diseases.